Throughout this application various patents and other publications are referred to in parenthesis. Full citations for the references may be found at the end of the specification. The disclosures of these patents and all patents, patent application publications and books referred to herein are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Macrophage migration inhibitory factor (MIF), a cytokine first identified in 1966, is expressed fairly ubiquitously and has both extracellular and intracellular roles (reviewed in (1)). MIF has been implicated in autoimmune and infectious disease, and cancer (reviewed in (1)). The causative role of MIF in cancer progression was initially linked to its increased expression by a variety of cancer cells, including prostate, colon, hepatocellular, lung, ovarian, in addition to melanoma, glioblastoma and neuroblastoma (2). In these cancers, MIF overexpression has been associated with a concomitant increase in: (a) tumor invasion/migration, (b) metastasis and (c) angiogenesis. More recent data have additionally identified the role of the host MIF in regulating tumor growth. In support of the latter, the role of MIF in regulating tumor angiogenesis in the B16-F10 melanoma model has recently been investigated (3). A combination either of B16-F10 or of shRNA targeting of MIF in the same melanoma cells with a MIF knockout (−/−) genetic background, resulted in significant reduction of tumor growth (by 47%), when compared to wild-type mice. Furthermore, reduced growth of CT26 colon tumors (by 75%) in MIF−/− mice was reported (4). Finally, host macrophage-produced MIF was shown to polarize tumor-associated macrophages (TAMs) towards an immunosuppressive M2 phenotype, whereas MIF inhibition or gene loss (MIF−/−) reversed TAM functionalities to M1-type (5). These studies, in conjunction with the previous reports, establish MIF as a promising anticancer drug-target.
An increase of MIF levels positively correlates with a poor prognosis in cancer (6-8). Anti-MIF neutralizing antibodies (Abs), MIF-directed siRNA/shRNA or anti-sense oligonucleotides and compounds hindering MIF secretion have been tested in vitro and in preclinical models with notable results (9,10). A more attractive approach to decrease MIF upregulation is the utilization of small molecule MIF inhibitors, which advantageously block the activity of both cancer cell- and host cell-secreted MIF. ISO-1, the “gold standard” inhibitor of MIF, was designed to selectively ligate the tautomerase catalytic site of MIF which is known to neutralize its pro-inflammatory activity (1,11,12). In vitro MIF reduction by ISO-1, has been reported to effectively reduce cancer cell proliferation, migration, and invasion of the human lung adenocarcinoma A549 (10,13) decrease the proliferation and invasiveness of prostate cancer DU-145 cells (9), restore contact inhibition of proliferation of LN229 and LN-18 glioblastoma cells (14), reduce cell migration and invasion of HS683 glioma cells (15), and suppress the proliferation of the murine colorectal cancer cells CT-26 (16). Previous studies have also addressed the role of ISO-1 in prostate and colorectal cancer in vivo (9,16). In both mouse models, ISO-1 treatment resulted in significant reduction of the tumor volume or weight, despite the lack of an optimal dosing regimen.
The present invention address the need for improved MIF inhibitors and improved cancer treatments employing MIF inhibitors.